Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
  • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to a novel use of a 15-keto-prostaglandin E compound as an endothelin antagonist.
• Endothelin is an endogenous bioactive peptide consisting of 21 amino acids, and three types of endothelin-11, endoselin-2 and endoselin-3 are known.
• Endothelin is a bioactive substance that directly or indirectly (regulates the release of various endogenous substances) and continuously contracts vascular and non-vascular smooth muscle. Endothelin production is enhanced by endothelial damage Is done. Its overproduction is hypertension, pulmonary blood pressure, Burger's disease, Reino's disease, asthma, fundus (retinal, choroid, etc.) disease, diabetes, arteriosclerosis, renal failure, myocardial infarction, angina, cerebrovascular It is thought to be one of the causes of spasms and cerebral infarction.
• Prostaglandins are a group of organic potent rubonic acids that are found in human and other mammalian tissues or organs and exhibit a wide range of physiological activities.
• Naturally occurring PGs have, as a general structural property, a prostanoic acid skeleton represented by the formula (A).
• PGFs are classified into ⁇ (hydroxyl group is in alpha configuration) and] 3 (hydroxyl group is in beta configuration) according to the configuration of the hydroxyl group at the 9-position.
• PGE "PGE 2 Oyobi PGE 3 vasodilation, hypotensive, gastric secretion decreasing, intestinal tract movement enhancement, uterine contraction, diuretic, are known to have a bronchodilating and anti-ulcer activity.
• PGF l C t , PGF 2 Hioyobi PGF 3 alpha is elevated blood pressure, vasoconstriction, intestinal tract hyperkinetic, uterine contractions, are known to have a luteolysis and bronchoconstriction activities.
• An object of the present invention is to provide an endoselin antagonist useful for treating various diseases and conditions involving endoselin. Furthermore, the present invention relates to a method for treating a disease caused by endothelin overproduction and the use of a 15-keto prostaglandin II compound for producing the above-mentioned endoselin antagonist.
• the present inventors have conducted intensive studies on the biological activity of the 15-keto-PGE compound, and have found that the 15-keto-PGE compound exhibits an extremely strong endothelin antagonism, thereby completing the present invention. That is, the present invention provides an endoselin antagonist comprising, as an active ingredient, a 15-keto prostaglandin II compound, except that a ct chain of prostanoic acid has a skeleton carbon atom of 8 or more. Since the endoselin antagonist of the present invention has an extremely strong endoselin antagonistic effect, it is effective in treating various diseases and conditions involving endothelin. “Treatment” as used herein includes any management, such as prevention, treatment, symptom relief, symptom reduction, progression arrest, etc.
• 15-keto prostaglandin E compound refers to the number of double bonds on ⁇ chain and ⁇ chain, the presence or absence of other substituents, Includes any substituent or derivative having an oxo group instead of a hydroxyl group at position 15 of the prostanoic acid skeleton, irrespective of the deformation of the upper part (excluding compounds with ⁇ -chain skeletal carbon atoms of 8 or more) .
• the number of carbon atoms is not limited by this in the present invention. That is, the number of carbons constituting the basic skeleton is 1 for carboxylic acid and 2 to 7 for carbon on the chain, 8 to 12 for carbon on the 5-membered ring, and 3 to 20 are added on the ⁇ chain, but when the number of carbons decreases on the chain, the names are deleted sequentially from the 2nd position. Similarly, the number of carbon atoms on the ⁇ chain When decreasing, the carbon number is sequentially reduced from the 20th position, and when increasing on the ⁇ chain, the 21st and subsequent carbon atoms are named as substituents. Unless otherwise specified, the configuration conforms to the configuration of the above basic skeleton.
• a 15-keto PGE compound having 10 carbon atoms in the ⁇ chain is referred to as a 15-keto 20-ethyl-PGE compound.
• compounds having a skeletal carbon atom on the ⁇ -carbon of 8 or more are outside the scope of the present invention.
• PGEs generally refer to compounds having an oxo group at the 9-position and a hydroxyl group at the 11-position of prostanoic acid, and the 15-keto prostaglandin ⁇ compound of the present invention corresponds to 1
• the 15-keto-PGE compound used in the present invention may be any PG derivative having an oxo group at the 15-position instead of a hydroxyl group and having a skeletal carbon atom number of 7 or less.
• the 15-keto PGE compound also includes a 13-, 14-dihydro 15-keto PGE compound in which the double bond at the 13-14 position is saturated.
• Representative examples that can be used in the present invention are 15-keto-PGE type 1, 15-keto PGE type 2, 15-keto PGE type 3, etc., and derivatives thereof.
• substituents or derivatives include compounds in which the carboxyl group at the terminal of the ⁇ -chain of the above 15-keto-PGs is esterified, a physiologically acceptable salt, and a carbon bond at the 2-3 position is doubled.
• hydroxy lower alkyl group examples include compounds having an alkyl group or a hydrogen atom.
• examples of the substituent bonded to the carbon atom at the 3-position, 17-position, 18-position and Z or 19-position include an alkyl group having 1 to 4 carbon atoms, particularly a methyl group, ethyl Group.
• examples of the substituent bonded to the carbon atom at position 6 include a lower alkyl group such as a methyl group and an ethyl group, a hydroxyl group, a halogen atom such as chlorine and fluorine, and an aryloxy group such as trifluoromethylphenoxy. can give.
• Examples of the substituent at the carbon atom at position 17 include halogens such as chlorine and fluorine.
• Substituents for the carbon atom at position 5 include halogen atoms such as chlorine and fluorine.
• the substituent at the carbon atom at the 6-position includes an oxo group forming a carbonyl group.
• a hydroxyl group, a lower alkyl group or a lower (hydroxy) alkyl substituent group is present at the carbon atom at position 11, the configuration of these groups may be ⁇ ,
• the derivative may have a compound such as an alkoxy group, a phenoxy group, or a phenyl group at the end of the ⁇ chain of a compound whose ⁇ chain is shorter than natural PGs.
• Preferred compounds include compounds having a lower alkyl group such as a methyl group and an ethyl group at the carbon at position 16, compounds having a halogen atom such as chlorine and fluorine, and compounds such as a methyl group and an ethyl group at the carbon at position 17.
• Particularly preferred compounds are 13-, 14-dihydro-15-keto PGE compounds in which the 13- to 14-position carbon bond is a single bond, and chlorine and fluorine at the 16-position carbon.
• Preferred compounds for use in this invention are those of formula (I)
• R is hydrogen, hydroxyl, hydroxy (lower) alkyl or lower alkyl
• A is one CH 2 OH, — COCH 2 OH, — CO OH or a functional derivative thereof
• B is one CH 2 — CH 2 —
• One CH CH—, one C ⁇ C—
• Q i and Q 2 are hydrogen, halogen or lower alkyl
• R 2 is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, aryl or aryloxy, saturated or unsaturated, lower to middle aliphatic hydrocarbon residue, lower cyclo An alkyl group, an aryl group or an aryloxy group]
• R 2 can, as bonds between carbon atoms in the main chain or side chain, at least one or more double bonds and the isolated Z or triple binding, separation Or it means to include continuously.
• the unsaturation between two consecutive positions is indicated by displaying the younger position number, and the unsaturation between two non-consecutive positions is indicated by displaying both position numbers.
• Preferred unsaturated bonds are a double bond at the 2-position and a double or triple bond at the 5-position.
• low to medium aliphatic hydrocarbon means a hydrocarbon having a straight or branched chain having 1 to 14 carbon atoms, with the proviso that the side chains have 1 to 3 carbon atoms. Preferably, it is a hydrocarbon having 2 to 10 carbon atoms.
• halogen includes fluorine, chlorine, bromine and boron.
• lower is intended to include groups having from 1 to 6 carbon atoms unless otherwise specified.
• lower alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, t
• lower alkoxy means lower alkyl-1 O-, wherein lower alkyl is as defined above.
• hydroxy (lower) alkyl means an alkyl as defined above substituted with at least one hydroxy group, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy and 1-methyl-. It is 1-Droquichetil.
• lower alkanoyloxy refers to a radical of the formula RCO-O-, where RCO- is an oxidized lower alkyl as defined above, eg, acetyl.
• lower alkyl group is a group formed by ring closure of a lower alkyl group having three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• aryl includes substituted or unsubstituted, aromatic carbocyclic or heterocyclic groups (preferably monocyclic groups) and includes, for example, phenyl, trinole, xylyl and phenyl.
• substituent include a halogen and a halogen-substituted lower alkyl group (here, the halogen atom and the lower alkyl group have the same meanings as described above).
• aryloxy refers to a radical of the formula ArO—, where Ar is an aryl radical as described above.
• the term "functional derivative" of the carboxyl group represented by A includes salts (preferably pharmaceutically acceptable salts), esters and amides.
• Suitable “pharmaceutically acceptable salts” include commonly used non-toxic salts, including salts with inorganic bases, such as alkali metal salts, thorium salts and potassium salts, etc., and alkaline earth metal salts (calcium salts).
• ammonium salts salts with organic bases, for example, amine salts (eg, methylamine, dimethylamine salt, cyclohexylamine) Salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylaminoamino) ethane salt, monomethylmonomonoethanolamine salt, lysine salt, proforce salt, Caffeine salts), basic amino acid salts (eg, arginine salts, lysine salts, etc.), and tetraalkylammonium salts.
• amine salts eg, methylamine, dimethylamine salt, cyclohexylamine
• benzylamine salt piperidine salt
• ethylenediamine salt ethanolamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylaminoamino) ethane salt, monomethylmonomonoethanolamine salt, lysine
• ester examples include lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butynole ester, isobutyl ester, t-butyl ester, pentyl ester, 1-cyclopropyl ethyl ester, and vinylol ester ester.
• lower alkynyl esters such as ethynyl esters and propynyl esters; hydroxy (lower) alkyl esters such as hydroxyethyl esters; methoxymethyl esters; and 1-methoxethyl.
• Aliphatic esters such as lower alkoxy (lower) alkyl esters such as esters, and phenyl esters, tosyl esters, t-petit / refeni / leestenole, salicinoleestenol, 3,4 Tokishifue two Noreesu ether, Benzuami Zadoff optionally ⁇ reel ester Le substituted such enyl ester, benzylidene Honoré esthetic Honoré, tri Chino Les Este Honoré, is Ari Le (lower) alkyl ester such as Benzuhi drill Honoré Este Honoré like.
• amide examples include mono- or di-lower alkylamides such as methylamide, ethylamide, and dimethylamide, arylamides such as anilide and toluidide, methylsulfonylamide, ethylsulfonylamide, and tolylsulfonylamide. And alkyl or arylsulfonylamides.
• R are hydrogen and a hydroxyl group, particularly preferably a hydroxyl group.
• A is 1COOH, pharmaceutically acceptable salts, esters and amides thereof.
• a preferred example of B is CH 2 —CH 2 —, which has a structure referred to as a so-called 13,14 dihedral type.
• Q 1 and Q 2 are that at least one is halogen, and preferably both are halogen. Particularly preferred is fluorine, and 16, 16-difluoro It has a structure called a mouth type.
• R 1 are hydrocarbons having 4 to 6 carbon atoms, particularly preferably 6 hydrocarbons.
• R 2 are hydrocarbons having 1 to 10 carbon atoms, particularly preferably hydrocarbons having 2 to 8 carbon atoms, and a structure having 1 or 2 side chains having 1 carbon atom is preferable.
• the configuration of the rings, ⁇ and Z or ⁇ chains may be the same as or different from the configuration of natural prostaglandins.
• the invention also encompasses mixtures of compounds having a natural configuration and compounds having a non-natural configuration. Examples of typical compounds of the present invention are 13, 14 dihydro-15-keto-16 mono- or difluoro-PGE compounds and derivatives thereof.
• 6-Okiso derivative delta 2 - derivatives, 3-methyl derivatives, 6-keto-induced body, 5- Furuoro derivatives, 5, 5-Jifuruoro derivatives, 1 7-methyl derivative, 1 8-methyl derivatives
• Examples include a 19-methyl derivative, a 20-methyl derivative, a 20-ethyl derivative, a 19-desmethyl derivative, and a 17-trinolue 17-phenyl derivative.
• the above 15-keto PGE compound is useful as an endothelin antagonist.
• the compound used in the present invention can be used as a drug for animals and humans, and is usually administered systemically or locally by ophthalmic, oral, intravenous (including infusion), subcutaneous, or rectal administration. used.
• the dose varies depending on the type of the subject such as an animal or a human, the age, the body weight, the condition to be treated, the desired therapeutic effect, the administration method, the treatment period, etc., but usually 0.01% for topical administration. ⁇ 100 ⁇ Eye dose or 2 to 4 divided doses daily or for systemic administration in sustained form 0.001 to 5
• a dose of 0 O mg / kg usually produces a sufficient effect.
• the eye drops according to the present invention include eye drops and eye ointments.
• Ophthalmic solutions are prepared by dissolving the active ingredient in a sterile aqueous solution, for example, a physiological saline solution, a buffer solution or the like, or by combining them for dissolution at the time of use.
• Ophthalmic ointments are prepared by mixing the active ingredient with a base.
• Solid compositions for oral administration according to the present invention include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like.
• the one or more active substances include at least one inert diluent, for example, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch. Mixed with polyvinylpyrrolidone and magnesium metasilicate aluminate.
• the composition may be formulated in accordance with conventional practice with additives other than inert diluents, such as lubricating agents such as magnesium stearate, disintegrating agents such as calcium fibrous dalconate, ⁇ , or ⁇ -cyclodextrin, and dimethyl monophenyl.
• an inclusion compound may be formed with the cyclodextrins to increase the stability in some cases.
• stability may be increased by ribosome formation using a phospholipid.
• Gastric-soluble resins such as sugar, gelatin, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate may be coated with a film of an enteric substance, or may be coated with two or more layers. . Furthermore, capsules made of a disintegrable substance such as gelatin may be used. If immediate action is required, sublingual tablets may be used. Glycerin, lactose and the like may be used as a base.
• liquid compositions for oral administration include emulsions, solutions, suspensions, syrups, and elixirs. It may contain a commonly used inert diluent, for example, purified water, ethanol and the like. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
• compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.
• Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• Aqueous solutions and suspension media include, for example, distilled water for injection, physiological saline and Ringer's solution.
• Examples of the medium for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbates, and the like.
• Such compositions may also contain adjuvants such as preservative I wetting agents, emulsifying agents and dispersing agents. These are sterilized by, for example, filtration through a bacteria retention filter, blending of a bactericide, gas sterilization or radiation sterilization. They can also be used to produce sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.
• suppository or pessary Another form is a suppository or pessary. These suppositories can be made by mixing the active ingredient with a base that softens at body temperature, such as liquor, and improve the absorbency by using a nonionic surfactant that has an appropriate softening temperature. May be.
• the reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography to give the title compound (2).
• dimethyl 3,3-difluoro-2-oxoheptylphosphonate (11.9) was added to a methylene chloride solution of thallium ethoxide (3.26 ml) and stirred for 1 hour.
• the mixture was cooled to 0 ° C., a solution of the aldehyde (3) prepared above in methylene chloride was added, and the mixture was stirred at room temperature for 14 hours.
• Acetic acid, celite and saturated aqueous potassium iodide were added to the reaction solution, and the mixture was filtered. The filtrate was treated by a conventional method, and the obtained crude product was subjected to column chromatography to give the title compound (4).
• Collins reagent was prepared using chromic anhydride (13.5 g) and pyridine (21.8 ml) in dichloromethane (30 Om 1). Celite (40 g) was added thereto, and the above benzyl ester (13) (2.550 g) was oxidized at -20 ° C.
• the crude product obtained after the ordinary treatment was purified by silica gel to give the title compound (14).
• PGE 2 benzyl ester (14) (1.550 g) was dissolved in acetic acid-THF-water (3-11-1, 50 ml) and kept at 50 ° C for 4 hours. Crude product obtained by conventional processing The product was purified by a silica gel column to give PGE 2 benzyl ester (15).
• PGE 2 benzyl ester (15) (0.844 g) was catalytically reduced using 5% palladium on carbon in ethyl acetate (30 ml). Column purification was performed to obtain 16,16-difluoro-13,14-dihydro-15-keto-PGEi (16).
• Beagle dogs male or female, body weight 8.2 to 11.8 kg were used as experimental animals.
• the animals were anesthetized by intravenous and subcutaneous administration of pentobarbital, and one side of the groin was incised to expose the femoral artery, for endothelin-1 (hereinafter simply referred to as ET-1) administration and arterial blood pressure.
• ET-1 endothelin-1
• a catheter for measurement was inserted and placed in each side branch of the femoral artery. After shaving the back of the hind limbs on both sides, a probe of a laser blood flow meter (ALF21D, manufactured by Advanced Technologies) was attached to the skin surface, and the blood flow rate of the skin tissue of the back was measured.
• ALF21D laser blood flow meter
• Test substance 1 0.3 Same as above 3
• Test substance 1 1.0 Same as above 3
• Test substance 1 13, 14-shi "Daito” P-15-keto 16, 16-shi “Fluoro-18S-meth. Stakuranshi”
• the compound used in the present invention is useful as an endoselin antagonist, and thus can be expected to be used for treatment or prevention of hypertension, Purger's disease, asthma, fundus disease and the like.

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